Project Summary/Abstract The 24 hour solar cycle is one of the most predictable, yet potentially damaging, aspects of life on Earth. Because of this, most animals utilize molecular circadian clocks which anticipate the rising sun and are prepared when the light is at its most UV-enriched. There are various ways in which this is achieved at the behavioral, anatomic, and physiologic levels. OPN5 is an opsin which is maximally sensitive to short- wavelength light. Recently, we found that OPN5 is a critical element in the mammalian retina?s ability to synchronize its local circadian rhythms to light cycles. The skin and the cornea are also daily exposed to sunlight in most animals, and both tissues contain robust, autonomous circadian clocks. We and others have observed the expression of OPN5 in both of these tissues. This proposal aims to characterize the role of these extraretinal OPN5 photoreceptors on the circadian rhythms of these tissues. Specifically, the aim of this project is to identify the specific cells in the skin and cornea that express OPN5, characterize their photic response, characterize the mechanism these cells use to disseminate photic information, and characterize the circadian nature of the light response that these tissues display. Using a mouse line from which a circadian luciferase reporter can be measured as a representation of clock gene expression, we have demonstrated that clocks in both skin and corneas can be synchronized by light and that this circadian photoreception is regulated by OPN5. This circadian reporter will be used to monitor tissues in culture, and a mouse line which includes a fluorescent protein only in OPN5 expressing cells will allow us to ascertain the precise identity of the extraretinal photoreceptor cells. Lastly, this proposal seeks to link the expression of extraocular photoreception to potential health risks. Skin, in particular, has been shown to have precise times of day when it is most vulnerable to UV light for development of skin cancer and erythema. This proposal will examine the role OPN5 plays in controlling timing of cell division, acute responses to UV light, the sensitivity during development, and the global transcriptional landscape of the skin and cornea. By analyzing the molecular state of tissues exposed to specific light conditions at various times of day we will gain a better understanding of the ways mammalian cells cope with high energy light, and we will begin to understand the way they use OPN5 to regulate circadian clocks to anticipate photic changes in their environment.